Comprehensive Review of Neurodegenerative Disorders

Abstract

Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's
disease and Amyotrophic Lateral Sclerosis, represent a significant and growing global health
challenge, particularly with aging populations. This review synthesizes current understanding, tracing
the historical recognition of these conditions to the complex molecular mechanisms now known to
drive neuronal loss. Key pathogenic processes discussed include protein misfolding and aggregation
(e.g., amyloid-beta, tau, alpha-synuclein, mutant huntingtin), oxidative stress linked to mitochondrial
dysfunction (often exacerbated by genetic factors like SOD1 mutations), chronic neuroinflammation
involving glial activation (microglia and astrocytes), and disruptions in proteostasis, particularly
impaired autophagy. While current treatments remain largely symptomatic, offering temporary relief
(e.g., cholinesterase inhibitors/memantine for Alzheimer's disease, levodopa for Parkinson's disease),
the focus is shifting towards disease-modifying strategies. This review highlights progress in
immunotherapies targeting protein aggregates (like Lecanemab /Donanemab for amyloid-beta,
Prasinezumab for alpha-synuclein), gene-targeted therapies using antisense oligonucleotides
(Tofersen for SOD1) and CRISPR/Cas9 systems (preclinical work on HTT and C9orf72) and stem
cell approaches using induced pluripotent stem cells. Diagnostic innovations, including advanced
PET imaging, fluid biomarkers (CSF Aβ/tau, blood NfL), and digital biomarkers, are improving early
detection and monitoring. Despite these advances, significant challenges such as disease
heterogeneity, blood-brain barrier penetration, biomarker limitations, and socioeconomic/ethical
hurdles impede clinical translation. Future directions emphasize personalized medicine, multi-target
therapies (multi-target direct ligands, combinations), repurposed drugs (Exenatide, Pridopidine),
natural compounds (Curcumin, Pingchan granule), pathway modulation (mTOR inhibitors), and
preventive strategies